Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. METHODS: We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. METHODS: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56-0.78; P<0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P<0.0001). CONCLUSIONS: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Ten-Year Outcomes After Coronary Artery Bypass Grafting According to Age in Patients With Heart Failure and Left Ventricular Systolic Dysfunction: An Analysis of the Extended Follow-Up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure).

BACKGROUND: Advancing age is associated with a greater prevalence of coronary artery disease in heart failure with reduced ejection fraction and with a higher risk of complications after coronary artery bypass grafting (CABG). Whether the efficacy of CABG compared with medical therapy (MED) in patients with heart failure caused by ischemic cardiomyopathy is the same in patients of different ages is unknown. METHODS: A total of 1212 patients (median follow-up, 9.8 years) with ejection fraction ≤35% and coronary disease amenable to CABG were randomized to CABG or MED in the STICH trial (Surgical Treatment for Ischemic Heart Failure). RESULTS: Mean age at trial entry was 60 years; 12% were women; 36% were nonwhite; and the baseline ejection fraction was 28%. For the present analyses, patients were categorized by age quartiles: quartile 1, ≤54 years; quartile, 2 >54 and ≤60 years; quartile 3, >60 and ≤67 years; and quartile 4, >67 years. Older versus younger patients had more comorbidities. All-cause mortality was higher in older compared with younger patients assigned to MED (79% versus 60% for quartiles 4 and 1, respectively; log-rank P=0.005) and CABG (68% versus 48% for quartiles 4 and 1, respectively; log-rank P<0.001). In contrast, cardiovascular mortality was not statistically significantly different across the spectrum of age in the MED group (53% versus 49% for quartiles 4 and 1, respectively; log-rank P=0.388) or CABG group (39% versus 35% for quartiles 4 and 1, respectively; log-rank P=0.103). Cardiovascular deaths accounted for a greater proportion of deaths in the youngest versus oldest quartile (79% versus 62%). The effect of CABG versus MED on all-cause mortality tended to diminish with increasing age (Pinteraction=0.062), whereas the benefit of CABG on cardiovascular mortality was consistent over all ages (Pinteraction=0.307). There was a greater reduction in all-cause mortality or cardiovascular hospitalization with CABG versus MED in younger compared with older patients (Pinteraction=0.004). In the CABG group, cardiopulmonary bypass time or days in intensive care did not differ for older versus younger patients. CONCLUSIONS: CABG added to MED has a more substantial benefit on all-cause mortality and the combination of all-cause mortality and cardiovascular hospitalization in younger compared with older patients. CABG added to MED has a consistent beneficial effect on cardiovascular mortality regardless of age. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Improved survival after acute graft-versus-host disease diagnosis in the modern era.

A cute graft-versus-host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft-versus-host disease. We examined outcome following diagnosis of grade II-IV acute graft-versus-host disease according to time period, and explored effects according to original graft-versus-host disease prophylaxis regimen and maximum overall grade of acute graft-versus-host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grade II-IV acute graft-versus-host disease (n=497 for 1999-2001, n=962 for 2002-2005, n=1,446 for 2006-2010). The median (range) follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the cohort with grade II-IV acute graft-versus-host disease, there was a decrease in the proportion of grade III-IV disease over time with 56%, 47%, and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively (P<0.001). Considering the total study population, univariate analysis demonstrated significant improvements in overall survival and treatment-related mortality over time, and deaths from organ failure and infection declined. On multivariate analysis, significant improvements in overall survival (P=0.003) and treatment-related mortality (P=0.008) were only noted among those originally treated with tacrolimus-based graft-versus-host disease prophylaxis, and these effects were most apparent among those with overall grade II acute graft-versus-host disease. In conclusion, survival has improved over time for tacrolimus-treated transplant recipients with acute graft-versus-host disease.

Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.

Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.

We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.

Effect of postremission therapy before reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia in first complete remission.

The impact of pretransplant (hematopoietic cell transplantation [HCT]) cytarabine consolidation therapy on post-HCT outcomes has yet to be evaluated after reduced-intensity or nonmyeloablative conditioning. We analyzed 604 adults with acute myeloid leukemia in first complete remission (CR1) reported to the Center for International Blood and Marrow Transplant Research who received a reduced-intensity or nonmyeloablative conditioning HCT from an HLA-identical sibling, HLA-matched unrelated donor, or umbilical cord blood donor from 2000 to 2010. We compared transplant outcomes based on exposure to cytarabine postremission consolidation. Three-year survival rates were 36% (95% confidence interval [CI], 29% to 43%) in the no consolidation arm and 42% (95% CI, 37% to 47%) in the cytarabine consolidation arm (P = .16). Disease-free survival was 34% (95% CI, 27% to 41%) and 41% (95% CI, 35% to 46%; P = .15), respectively. Three-year cumulative incidences of relapse were 37% (95% CI, 30% to 44%) and 38% (95% CI, 33% to 43%), respectively (P = .80). Multivariate regression confirmed no effect of consolidation on relapse, disease-free survival, and survival. Before reduced-intensity or nonmyeloablative conditioning HCT, these data suggest pre-HCT consolidation cytarabine does not significantly alter outcomes and support prompt transition to transplant as soon as morphologic CR1 is attained. If HCT is delayed while identifying a donor, our data suggest that consolidation does not increase transplant treatment-related mortality and is reasonable if required.

Allotransplantation for patients age ≥40 years with non-Hodgkin lymphoma: encouraging progression-free survival.

Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ≥40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ≥65; P = .0008). Fewer patients aged ≥65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ≥65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ≥65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ≥55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ≥55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL.

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two 6-month, phase 3 studies.

BACKGROUND: Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. METHODS: Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. RESULTS: Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). CONCLUSIONS: PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

Reliability of the EasyAngle® for Assessing Hip Range of Motion in Healthy Children.

Background: The use of digital goniometry has emerged as a viable alternative to universal goniometry for assessing hip range of motion (ROM). However, few studies have assessed the use of digital goniometry in pediatric populations and there are a limited number of studies that investigate any one device. The EasyAngle® is a digital goniometer that may be beneficial for use in pediatric settings as it requires only one hand to operate the device. Purpose: The purposes of this study were 1) to establish the intrarater and interrater reliability of the EasyAngle® digital goniometer in measuring hip joint ROM in healthy elementary school-aged children, and 2) to establish preliminary normative reference values for each year of age using the EasyAngle® for hip joint ROM in healthy elementary school-aged children. Study Design: Descriptive Laboratory Study. Methods: Passive hip ROM (flexion, abduction, extension, internal rotation, external rotation) was measured on each leg of healthy participants using the EasyAngle®. A total of 40 hip joints were measured. Two blinded raters conducted three trials of each hip motion on both legs. Intrarater and interrater reliability of the recorded hip range of motion were calculated using intra-class correlation coefficients (ICC) (3,1). Results: Twenty healthy children were measured (age 5-10, mean = 7.40 years old, SD = 1.37, 9 males, 11 females). Mean hip ROM was reported by age. Intrarater and interrater reliability were good to excellent for all hip ROM measurements (0.81-0.97 intra rater; 0.77- 0.91 interrater). Hip flexion had the strongest intrarater (0.96, 0.97) and interrater reliability (0.91). Intrarater reliability was lowest for hip abduction for Rater 1 and hip extension for Rater 2. Interrater reliability was lowest for hip external rotation (0.78). Conclusion: The EasyAngle® is a reliable tool for assessing hip range of motion in healthy children ages 5-10. Normative hip ROM values using the EasyAngle® are available to clinicians. Level of Evidence: Level 3- Reliability study.

A Phase 3, Randomized, Double-Blind, Sham-Controlled Trial of SI-6603 (Condoliase) in Patients With Radicular Leg Pain Associated With Lumbar Disc Herniation.

BACKGROUND CONTEXT: SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH. PURPOSE: The Discover 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH. STUDY DESIGN/SETTING: A randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States. PATIENT SAMPLE: Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks. OUTCOME MEASURES: The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings. METHODS: Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery. RESULTS: Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=0.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=0.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=0.0223) and Week 52 (p=0.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred. CONCLUSIONS: Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies.

A randomized, placebo-controlled trial of long-acting dexamethasone viscous gel delivered by transforaminal injection for lumbosacral radicular pain.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03372161.

Providing personalized prognostic information for adult leukemia survivors.

Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least 1 year after allogeneic hematopoietic cell transplantation is difficult. We analyzed 3339 patients with acute myeloid leukemia and 1434 patients with acute lymphoblastic leukemia who received myeloablative conditioning and related or unrelated stem cells from 1990 to 2005. Most clinical factors predictive of LFS in 1-year survivors were no longer significant after 2 or more years. For acute myeloid leukemia, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS 2 or more years after transplantation. For lymphoblastic leukemia, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for 1 year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present and higher if noncyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator (http://www.cibmtr.org/LeukemiaCalculators). This prognostic information is more relevant for survivors than estimates provided before transplantation.

Cardiovascular safety of varenicline: patient-level meta-analysis of randomized, blinded, placebo-controlled trials.

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Reduced Trial.

BACKGROUND: There is limited published information on outcome adjudication in heart failure (HF). OBJECTIVES: The authors sought to compare investigator reports (IRs) to a Clinical Events Committee (CEC) and the impact of SCTI (Standardized Clinical Trial Initiative) criteria. METHODS: In the EMPEROR-Reduced trial, the authors compared IRs to the CEC for concordance; treatment effect on primary composite outcome events; and the components first event hospitalization primarily for HF or cardiovascular mortality (CVM), prognosis after hospitalization for heart failure (HHF), total HHFs, and trial duration with and without SCTI criteria. RESULTS: The CEC confirmed 76.3% of IR events for the primary outcome (CVM: 89.1%; HHF: 73.7%). The HR for treatment effect did not differ between adjudication methods for the primary outcome (IR: 0.75 [95% CI: 0.66-0.85]; CEC: 0.75 [95% CI: 0.65-0.86]), its components, or total HHFs. The prognosis after first HHF for all-cause mortality and CVM also did not differ between IR or CEC. Interestingly, IR primary HHF with different CEC primary cause had the highest subsequent fatal event rate. Full SCTI criteria were present in 90% of CEC HHFs-with a similar treatment effect to non-SCTI. The IR primary event reached the protocol target number (841) 3 months earlier than CEC (4 months with full SCTI criteria). CONCLUSIONS: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation. The use of granular (SCTI) criteria did not improve trial performance. Finally, our data suggest that consideration be given to broadening the HHF definition to include "for or with" worsening disease. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit.

BACKGROUND: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. METHODS: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. RESULTS: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. CONCLUSIONS: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications.

Therapies activating the immune system (checkpoint inhibitors) have revolutionized the treatment of patients with advanced cancer, however new molecular tests may better identify patients who could benefit. Using treatment data and clinical molecular test results, we report the development and validation of Immunotherapy Response Score (IRS) to predict checkpoint inhibitor benefit. Across patients with more than 20 advanced cancer types, IRS better predicted checkpoint inhibitor benefit than currently available tests. Data from >20,000 patients showed that IRS identifies ~8% of patients with advanced cancer who may dramatically benefit from checkpoint inhibitors but would not receive them today based on currently available tests. Our approach may help clinicians to decide which patients should receive checkpoint inhibitors to treat their disease.

Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit.

Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment. Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.

Outcome of lower-intensity allogeneic transplantation in non-Hodgkin lymphoma after autologous transplantation failure.

We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach.

Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study.

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.

Quantification of Branched-Chain Amino Acids in Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Branched-chain amino acids (BCAA), including valine, alloisoleucine, isoleucine, and leucine, play significant roles in a number of metabolic pathways in the body. Deficiency in branched-chain ketoacid dehydrogenase complex, an enzyme required for metabolism of those amino acids, will lead to elevation and accumulation of BCAA and ketoacids in bodily fluids. This results in maple syrup urine disease (MSUD), a condition estimated to affect 1 in 100,000-300,000 births. If MSUD is not diagnosed in the first few days of life, progression of this disease can lead to intellectual disability, coma, irreversible brain damage, seizures, or even death. If diagnosed early, MSUD can be managed by monitoring the blood concentrations of BCAA and adjusting the patient's dietary intake accordingly. Therefore, it is critical to have a rapid, accurate, and reliable BCAA assay for confirmation of MSUD in newborns as well as routine monitoring of MSUD patients. Here, we describe a high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method for BCAA measurement which requires only 20 µL of plasma. The sample preparation does not require derivatization and only involves protein precipitation with LC/MS-grade methanol, which contains leucine(13C6;15N), isoleucine(13C6;15N), and valine(13C5;15N) as the internal standards. The final sample extracts do not require dry-down and reconstitution and are readily compatible with the liquid chromatography (LC) method. BCAA are separated using the isocratic gradient method on a mixed-mode Intrada column. Multiple-reaction monitoring (MRM) mode is used for MS/MS detection to monitor the parent-to-daughter transitions m/z 132.2 to 86.4 for leucine, isoleucine, and alloisoleucine; m/z 118.2 to 72.4 for valine; m/z 139.2 to 92.4 for leucine(13C6;15N) and isoleucine(13C6;15N); and m/z 124.2 to 77.4 for valine(13C5;15N).